Source 丨21 Healthnews21 original work
Author 丨 Zhu Ping
Editor 丨Xu Xu
Image source 丨 Figureworm
"Stem cells treated Rene Liu's knee well", "Stem cells allowed Che Wang Schumacher to restore consciousness"... For stem cell therapy, there are countless legends in society, and in the fields of medicine, health care, and beauty, it is also declared by some people as an "omnipotent miracle drug or therapy".
In fact, since the day they were discovered, stem cells have been pinned on the "ultimate dream" of human health, which is mainly determined by the function of stem cells themselves.
Recently, Dr. Wang Xiaofang, co-founder and chief technology officer of Emstein Biotechnology Co., Ltd., also described the prospect of stem cell therapy in an exclusive interview with the 21st Century Business Herald reporter: "In the future, stem cells can modify specific expressed proteins, certain genes, and the liver has a problem, and a younger and healthier liver can be replaced by stem cells; in addition to the more complex brain nerves, theoretically can be solved by stem cells." ”
Not long ago, the world-renowned pharmaceutical company Vertex released the latest clinical trial data on the allogeneic stem cell therapy VX-880 for the treatment of type 1 diabetes, which proved for the first time that stem cell therapy can restore islet cell function in patients with type 1 diabetes. The subjects of the Phase I clinical trial of The new stem cell drug IMS001 (T-MSC), the world's first intravenous infusion embryonic stem cell source, are also officially enrolled in the Phase I clinical trial of the stem cell new drug for multiple sclerosis (MS).
While the medical community continues to explore and study stem cell research, some merchants also use this as a gimmick to make money, and "100,000 yuan a shot of stem cell injection" floods some hospitals, clinics, and beauty salons. Some enterprises engaged in stem cell research also use the application of stem cells in the field of medical aesthetics as a breakthrough point to generate income.
In this regard, Wang Xiaoxiang pointed out to the 21st Century Business Herald reporter that the state explicitly prohibits the use of stem cells as cosmetic raw materials for market development or application, if used in medical beauty projects, it is necessary to carry out clinical phase III trials according to drugs, and there are not many clinically approved stem cell treatment products, and the technology is still constantly improving. "The industry is just in its infancy, and governments are also regulating and encouraging. As a relatively new industry, there is still a long way to go. It's a very early stage, but it requires businesses to have new, better technology than the original. ”
"The Ultimate Dream"
Stem cells are a group of cells with self-renewal and multi-directional differentiation potential, mainly derived from cord blood, bone marrow, peripheral blood, embryos and pulp, etc., which can be further differentiated into multiple types of cells, constituting a variety of complex tissues and organs of the body.
Wang Xiaoxiang said in the 21st Century Business Herald reporter that stem cells are divided into embryonic stem cells and adult stem cells (including mesenchymal stem cells, adipose stem cells, hematopoietic stem cells, etc.), the former is a totipotent stem cell, which can theoretically differentiate into all cells, and the latter is a pluripotent stem cell, which can only differentiate into mesoderm cells, such as bone, cartilage, and fat. Embryonic stem cells can be passed on indefinitely, while the latter can pass on a finite number of generations.
Adult stem cells, that is, undifferentiated cells found in an already differentiated tissue, are relatively easy to obtain, there are no ethical issues, there is no histocompatibility, and the risk of tumorigenesis is theoretically very low. However, the isolation and in vitro culture of adult stem cells have not yet been fully resolved, and in some genetically defective diseases, genetic errors may appear in patients.
Wang Xiaofang pointed out that the development of adult-derived mesenchymal stem cells has now encountered bottlenecks in foreign countries, because the source of such cells is unstable, and the large-scale expansion and increase in vitro production cannot meet the requirements, but there is also a certain application space, that is, the autologous stem cell treatment part. "So the latest trend is to use totipotent stem cells, including embryonic stem cells, induced pluripotent stem cells, nuclear transfer stem cells, the biggest feature of these cells is that they can be infinitely expanded in vitro, with the potential to differentiate into almost all tissues and cells in the human body."
It is understood that from 1968, hematopoietic stem cells were applied to the first case of bone marrow transplantation, stem cell medical technology applications began to develop rapidly, in 1998, American scientists found that can be isolated, in vitro culture of human embryonic stem cells, embryonic stem cells from early embryos, with a strong value-added ability, differentiation ability, but facing a series of ethical problems.
In 1999, stem cell therapy was listed by Science as the first of the top ten scientific achievements of that year because of its bright therapeutic prospects, and then in 2006, Shinya Yamanaka, a professor at Kyoto University in Japan, obtained induced pluripotent stem cells for the first time through genetic technology, avoiding ethical issues and winning the Nobel Prize.
Wang Xiaoxiang pointed out to the 21st Century Business Herald reporter that compared with traditional drugs, stem cell therapy is actually traded in with the old. "In the future, combined with tissue engineering, artificial organs can be made, which is actually subversive to the entire concept of regenerative medicine and treatment."
Wang Xiaofang further introduced that at present, many large-scale clinical trials have shown that the overall safety of stem cells is actually much higher than that of traditional chemical drug antibody drugs, and it is a treatment method that is more integrated with their own biological tissues, so the overall safety is much better than traditional drugs.
"Stem cells have far fewer side effects than traditional medicines. The main concern is whether there is tumorigenicity, at present, whether it is autologous stem cells or allogeneic stem cell treatment, tumorigenicity is very low, so far there have been no relevant reports. In addition, it is necessary to pay attention to whether there is an acute immune response or some other safety hazards. Wang Xiaoxiang said to the 21st Century Business Herald reporter.
Deep blue sea
With the advancement of stem cell therapy technology, stem cells can play a role in almost all major diseases of human beings in the future. Wang Xiaofang pointed out that stem cell therapy can differentiate all the desired organs and tissues through cells, which will be a revolutionary innovation in the way diseases are treated. Its market potential is also considered to be a blue ocean to be deeply developed.
The development of the stem cell medical industry chain involves stem cell storage, stem cell drug development, and stem cell therapy, and the development space in the next three directions is huge.
There are reports that the global stem cell market will reach $400 billion in the future. In 2001, the global stem cell market size was about 330 million US dollars, nearly 1 billion US dollars in 2004, nearly 2 billion US dollars in 2007, and 250 billion US dollars in 2014. According to experts at the 2014 International Symposium on Cell Therapy, the global stem cell industry is expected to reach $400 billion by 2020.
According to QYResearch's research data, from 2020 to 2026, the compound growth rate of China's stem cell medical industry market size is about 15%, and in the next few years, the proportion of China's stem cell medical industry market size in the global market size will further increase. It is conservatively estimated that by 2026, the market size of China's stem cell medical industry will reach 32.5 billion yuan.
Zheshang Securities Research Institute also analyzed that in 2009, the income of China's stem cell industry was about 2 billion yuan, and in 2015 it has reached 30 billion yuan, with an annual compound growth rate of more than 50%. Driven by five major factors such as loose supervision and market objective demand, the market will grow geometrically, and it is predicted that by 2020, the industry market size will reach about 230 billion yuan. In the next few years, the industry will also develop rapidly, with large market demand and broad prospects.
Although the market demand is huge, so far very few stem cell drugs have completed Phase III clinical trials, and it is reported that around the world, the main focus is on a small number of indications such as orthopedic rehabilitation, ulcers, and graft-versus-host disease.
For example, Arnold Kaplan, an American biologist and the name of mesenchymal stem cells and known as the "father of mesenchymal stem cells", founded Osiris Therapeutics, the world's first mesenchymal stem cell company. In 2012, 21 years after he named the stem cells, one of the company's related drugs was approved for marketing in Canada for graft-versus-host disease.
In addition to the above indications, many companies are also deployed in other areas. For example, not long ago, Vertex published the first day positive data for patients with type 1 diabetes in the phase I/II clinical trial of VX-880 (stem cell-derived totally differentiated islet cell replacement therapy). On the 90th day of treatment with VX-880, the patient's insulin production resumed, the daily insulin requirement was reduced by 91%, and blood glucose control was significantly improved and well tolerated. This is the first time stem cell therapy has been demonstrated to restore islet cell function in patients with type 1 diabetes.
And Eimstein is also in the inflammatory bowel disease, cerebral infarction, Parkinson's, lupus erythematosus, diabetes and other major aspects of cooperation with some domestic scientific research institutions, clinical, hospitals, colleges and universities are cooperating to do research in this area, Wang Xiaoxiang 21st Century Business Herald reporter said that Emstein will have a lot of pipelines in the future, will be for more than 150 kinds of human autoimmune diseases to choose more suitable for some of the more suitable indications for testing.
Currently, multiple sclerosis research is the fastest growing in Einstein. The reason why multiple sclerosis was chosen as the breakthrough first, Wang Xiaofang explained that the disease is a rare disease in China, but there are actually more than 5 million patients in the world and more than 1 million patients in the United States. "When I was studying abroad, many laboratories in American university research institutes were studying this disease. We have also been studying, including the mechanism, the treatment model. ”
It is understood that Wang Xiaofang is the founding shareholder of Eimstein, the chief technology officer of Einstein, the chief scientist of T-MSC technology, and the key inventor of T-MSC technology, and the technology has obtained 12 invention patents. He holds a Ph.D. in Immunology from Peking University School of Medicine; a Ph.D. in Immunology from the University of Texas at Houston Health Science Center; and a postdoctoral fellow at Yale University and the University of Connecticut.
Wang Xiaofang studied under Professor Xu Renhe, Xu Renhe's embryonic stem cell serum-free culture technology has become the mainstream technology in the industry, and is also the earliest researcher of james Thomson research institute, the father of human embryonic stem cells, with more than 10 core invention patents, more than 80 papers published, and more than 7,000 citations. Xu Renhe is currently the Vice Dean and Distinguished Professor of the School of Health Sciences at the University of Macau, and a former professor at the University of Connecticut and director of the Stem Cell Center.
"Multiple sclerosis currently has no particularly effective treatment, it is some symptomatic treatment, which can only alleviate the disease and delay the frequency of onset." Patients eventually progress to worsening and then to incapacity. When doing animal tests, we found that our self-developed T-MSC cells have a much better effect than some of the previously commonly used MSCs, and T-MSC mesenchymal stem cells may have a better clinical effect on this disease. Wang Xiaofang introduced.
"Some of the previous drugs were basically designed for one or two targets as symptomatic treatments, and there were many side effects. Stem cell therapy has a variety of mechanisms working simultaneously and has the function of inducing immune tolerance for a long time. Multiple sclerosis is an autoimmune disease, an autoimmune disease is a disease caused by the body's immune response to its own antigens and causing damage to its own tissues. If the immune system can be retrained so that immune-tolerant lymphocytes stop attacking their own proteins and antigens, the disease can be prevented from recurring. Wang Xiaofang further introduced.
It is understood that the above-mentioned multiple sclerosis stem cell treatment is currently in the first phase of the clinical trial abroad, which takes about 2 years to complete; the second phase of the clinic also takes about 2 years, and the phase III clinical is almost 2 to 3 years. In the United States, because it is not a rare disease, it must be completed in phase III before it can be listed. It will take about five or six years in the United States.
In China, Emstein also held a Pre IND (New Drug Registration Application) meeting with the China Drug Evaluation Center, and it is expected to complete the preparation of all materials early next year, followed by a formal IND submission, and if it goes well, it should be able to enter the Chinese IND in the second quarter of 2022. Multiple sclerosis is a rare disease in China, there is a green channel, and there is hope of listing in about 4 years.
Two paths
In fact, the regulation of stem cell therapy has been controversial for a long time, whether as a therapy or a drug.
In the process of this debate, in many countries, stem cells have been advertised by some companies as "omnipotent miracle drugs or therapies", involving disease treatment, health care, beauty and other fields.
Previously, for a long time, the regulatory idea of "stem cells are medical means rather than drugs" dominated, beauty institutions "100,000 yuan a stem cell beauty needle", stem cell banks across the country, various hospitals have also launched their own stem cell clinical treatment services, advocating that stem cell therapy can cure cancer, diabetes, hepatitis and other "difficult diseases".
In 2012, Feng Shiliang, a member of the National Committee of the Chinese People's Political Consultative Conference and president of the Liaoning Provincial Diabetes Treatment Center, quoted an oil poem to describe the management problems of the stem cell industry in a proposal for the two sessions of the National People's Congress: "The science and technology department strives to run 'encourage dry', the health department closes its eyes and 'does not let it dry', the drug regulatory department looks at the United States 'looking at the dry', scholars and experts advocate the belief of 'bold dry', business owners seek profits and avoid harm 'faint dry', medical institutions chase after fame and profit 'steal dry', beauty institutions talk nonsense 'flicker dry', tens of thousands of patients are made into white rats." 'Spend money to do it'. ”
In April 2012, Nature also published an article describing the stem cell chaos in China, noting that several companies "advertised treatments for serious diseases such as Parkinson's disease, diabetes and autism on their websites and attracted thousands of medical tourists from overseas."
To this end, the then Ministry of Health and the State Food and Drug Administration changed the research and development of stem cell drugs from standardized rectification to comprehensive suspension, and the 10 applications for the registration of stem cell drugs accepted by the Food and Drug Administration from 2004 to 2012 were all cleared, and a number of standardized documents were drafted and released.
For example, in 2015, China's first normative document for the management of stem cell clinical research was released, "Notice on carrying out the Filing of Stem Cell Clinical Research Institutions"; at the end of 2017, the "Technical Guidelines for Cell Product Research and Evaluation (Trial)" was introduced, and the research and registration application of cell therapy products was restarted. This has also been interpreted by the industry as a turning point in cell therapy policy. In June 2018, the first application for the registration of the new drug "human pulp mesenchymal stem cell injection" in China was also accepted.
In 2020, the Ministry of Science and Technology issued the Notice of the Ministry of Science and Technology on Issuing the 2020 Annual Project Application Guidelines for Key Special Projects such as the National Key Research and Development Plan "Stem Cell and Transformation Research", and the total allocation of funds nationwide reached 240 million yuan. At the same time, the Drug Evaluation Center of the State Drug Administration organized the drafting of the "Technical Guidelines for Clinical Trials of Human Stem Cells and Their Derived Cell Therapy Products (Draft for Comment)" in order to provide more targeted suggestions and guidelines for drug research and development registration applicants and researchers carrying out drug clinical trials.
Wang Xiaoxiang pointed out to the 21st Century Business Herald reporter that the current national policies are good for stem cell treatment enterprises, especially in the past two years, the clinical path is becoming more and more standardized, and the "dual-track system" supervision of stem cells according to drug and technology management is clearly defined in China. Stem cell preparations of enterprises are encouraged to be declared according to drugs and supervised by the State Food and Drug Administration; new biomedical technologies led by medical institutions, that is, hospital preparations can be managed according to medical technology and supervised by the Health Commission.
Wang Xiaofang analyzed that China's regulatory approach is actually a combination of two major methods in the international market, on the one hand, according to the "strict management" form in the United States, that is, it is necessary to do clinical phase 1, 2, and 3 trials, which are regulated by drugs; Japan, Australia, the United Kingdom and other countries can be regulated by medical technology, that is, they do not need the approval of a central government regulatory department, and only through the hospital's ethics committee can approve and then can carry out clinical trials faster.
"China has learned from the advantages of two approaches, namely new drug approval and clinical filing." Wang Xiaofang believes that the State Food and Drug Administration and the National Health Commission should try to encourage innovation in the control of specific projects and try to encourage innovation under the condition of controllable risks, which will promote the development of the entire industry faster.
What makes Wang Xiaofang happy is that China also attaches great importance to the protection of intellectual property rights in the field of stem cells. This is actually the key to protecting innovation.
In 2018, the State Intellectual Property Office issued the Catalogue of Key Industries Supported by Intellectual Property Rights (2018 Edition), which clearly listed stem cells and regenerative medicine, immunotherapy, and cell therapy as one of the key industries in national key development and urgent need of intellectual property support.
At the same time, Wang Xiaofang also pointed out that the main intellectual property protection of stem cells is the entire process of cell production and technology development. Compared with the targets of antibodies and genes that are not protected by patents, it is difficult to form barriers in intellectual property rights, and stem cell production has many technical barriers, once a new technology is made, it is not easy for other companies to copy.
However, although stem cell therapy can be expected in the future and the national policy is favorable, due to the long drug research and development cycle, many capital is prohibitive, but choose to invest in some relatively late projects, which can see the benefits as soon as possible.
In this regard, Wang Xiaoxiang introduced to the 21st Century Business Herald reporter that in foreign countries, most of the companies that do early drug development must continue to raise funds through listing for follow-up research and development. According to statistics done abroad, although there is a risk of failure in early drug development, the actual overall yield of angel investment or early project investors is higher than the yield of late investment.
"Although innovative drugs, including stem cell therapies, take a long time to market and approve, according to international practice, there are also multiple channels for early project commercialization. For example, in different development processes, a reasonable valuation can be obtained through listing financing, that is, raising funds in the capital market for research and development to carry out clinical trials; innovative pharmaceutical companies can also cooperate with some traditional pharmaceutical companies to develop multiple pipelines, so as to obtain early milestone payments to obtain certain revenue support for subsequent development and accelerate the advancement of drugs. Wang Xiaoxiang said to the 21st Century Business Herald reporter that he hopes that China's investment institutions can increase investment in innovative technologies.